Linagliptin-containing orally disintegrating tablets

Abstract

The present invention provides: a linagliptin-containing orally disintegrating tablet which is capable of sufficiently masking bitterness; and a method for producing the same. According to an embodiment of the present invention, provided is a linagliptin-containing orally disintegrating tablet containing: linagliptin; and an additive including at least one selected from the group consisting of carmellose calcium, crosscarmellose sodium, carmellose, and sodium starch glycolic acid. The additive may also include at least one selected from the group consisting of carmellose calcium, crosscalmellose sodium, and carmellose.

Description

TECHNICAL FIELD

[0001] The present invention relates to a linagliptin-containing orally disintegrating tablet and a method for producing the same. BACKGROUND ART

[0002] Linagliptin (1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine) is a dipeptidyl peptidase-4 (DPP-IV) inhibitor and is used as a therapeutic agent for type II diabetes. Patent Document 1 discloses a pharmaceutical composition comprising linagliptin or a salt thereof, a first diluent which is mannitol, a second diluent which is pregelatinized starch, a binder which is copovidone, a disintegrant which is corn starch, and a lubricant which is magnesium stearate.

[0003] On the other hand, for the purpose of improving ease of administration and the like, it is desired that the linagliptin-containing preparation be made into an orally disintegrating tablet, which is a dosage form easy to take for the elderly, patients with dysphagia, and the like. In particular, in the case of type II diabetes treatment, since medication is required over a long period of time, orally disintegrating tablets that are easy to take are expected to lead to patients' active participation in treatment and improved medication adherence. Orally disintegrating tablets are required to have good administration feel such as taste in addition to rapid disintegratability, and when the active pharmaceutical ingredient has a bitter taste or the like, masking of the bitter taste or the like is required. In formulating a linagliptin-containing preparation into an orally disintegrating tablet, since linagliptin has a strong bitter taste, a contrivance for masking the bitter taste of linagliptin is necessary.

[0004] As one means of masking bitterness, for example, Patent Document 2 reports a technique of coating particles containing the active pharmaceutical ingredient with a poorly soluble substance. For example, Patent Document 3 discloses a method of processing a mixture of an anionic (meth)acrylate copolymer and a pharmaceutical active substance into granules or powder without adding a basic active substance by melting the mixture, extruding the mixture, and finely grinding the extruded material into granules or powder. For example, Patent Document 4 discloses a method of making drugs with an unpleasant taste easier to take by mixing them with sucralose, a water-soluble sweetener, to suppress the unpleasant taste of drugs when taken. The above conventional methods of masking bitterness are complicated, time-consuming, and require special manufacturing equipment, such as coating fine particles containing the active pharmaceutical ingredient or melting, extrusion, and grinding processes. Therefore, there is a need for a simple and efficient method of masking bitterness. [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] Patent No. 5478244 [Patent Document 2] Special Publication No. 6-502194 [Patent Document 3] Special Publication No. 2005-526731 [Patent Document 4] Japanese Patent Publication No. 2001-342151 [Overview of the project] [Problems that the invention aims to solve]

[0006] One of the objectives of this invention is to provide a linagliptin-containing orally disintegrating tablet capable of sufficiently masking bitterness, and a method for producing the same. [Means for solving the problem]

[0007] According to one embodiment of the present invention, a linagliptin-containing orally disintegrating tablet is provided, comprising linagliptin and an additive comprising one or more selected from the group consisting of carmellose calcium, croscarmellose sodium, carmellose, and sodium starch glycolate.

[0008] The additive may include one or more selected from the group consisting of carmellose calcium, croscarmellose sodium, and carmellose.

[0009] The additive may be croscarmellose sodium.

[0010] The additive may be present in an amount of 0.5 parts by weight or more per 1 part by weight of linagliptin. [Effects of the Invention]

[0011] One embodiment of the present invention provides a linagliptin-containing orally disintegrating tablet capable of sufficiently masking bitterness, and a method for producing the same. [Modes for carrying out the invention]

[0012] The linagliptin-containing orally disintegrating tablets and their manufacturing method according to the present invention will be described in detail below. However, the linagliptin-containing orally disintegrating tablets and their manufacturing method according to the present invention are not limited to the descriptions of the embodiments and examples shown below.

[0013] As a result of our investigations, we found that when we manufactured linagliptin-containing orally disintegrating tablets containing a specific disintegrant, we were able to suppress the bitterness derived from linagliptin. This means that by selecting and including a specific disintegrant, we were able to suppress the bitterness derived from linagliptin in linagliptin-containing orally disintegrating tablets, regardless of the manufacturing method.

[0014] An orally disintegrating tablet containing linagliptin according to one embodiment of the present invention contains linagliptin and a disintegrant other than crospovidone.

[0015] The linagliptin in this embodiment is 1-[(4-methyl-quinazoline-2-yl)methyl]-3-methyl-7-(2-butyne-1-yl)-8-(3-(R)-amino-piperidine-1-yl)-xanthine. However, it is not limited to this, and any linagliptin, a salt thereof, or a hydrate thereof may be used. Linagliptin is contained in, for example, 5 mg per tablet of the linagliptin-containing orally disintegrating tablet according to the present invention.

[0016] The disintegrant in this embodiment preferably contains one or more selected from the group consisting of carmellose calcium, croscarmellose sodium, carmellose, and sodium starch glycolate. More preferably, the disintegrant contains one or more selected from the group consisting of carmellose calcium, croscarmellose sodium, and carmellose. The additive is more preferably croscarmellose sodium.

[0017] In this embodiment, the disintegrant is preferably present in an amount of 0.5 parts by weight or more per 1 part by weight of linagliptin. It is preferable that the disintegrant is present in an amount of 0.9 parts by weight or more per 1 part by weight of linagliptin. It is preferable that the disintegrant is present in an amount of 1.8 parts by weight or more per 1 part by weight of linagliptin. It is more preferable that the disintegrant is present in an amount of 2 parts by weight or more per 1 part by weight of linagliptin. It is preferable that the disintegrant is present in an amount of 10 parts by weight or less per 1 part by weight of linagliptin. It is preferable that the disintegrant is present in an amount of 6 parts by weight or less per 1 part by weight of linagliptin.

[0018] The linagliptin-containing orally disintegrating tablets of this embodiment contain additives necessary to form orally disintegrating tablets. Examples of additives include excipients, binders, disintegrants other than crospovidone, lubricants, surfactants, sweeteners, flavoring agents, fragrances, colorants, etc. Additives can be used individually or in combination of two or more. In the case of two or more additives, a so-called premix additive, which is a mixture of multiple additives granulated in advance, may also be included.

[0019] The additives in this embodiment include, for example, starches such as corn starch, lactose, sucrose, mannitol, xylitol, erythritol, sorbitol, maltitol, calcium citrate, calcium phosphate, crystalline cellulose, magnesium carbonate, calcium carbonate, magnesium aluminometasilicate, light anhydrous silicic acid, anhydrous calcium hydrogen phosphate, and other excipients; sucrose, gelatin, acacia powder, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyethylene glycol, carmellose, crystalline cellulose / carmellose sodium, carmellose sodium, dextrin, pullulan, tragacanth, sodium alginate, pregelatinized starch, and other binders; magnesium stearate, calcium stearate, stearyl sodium fumarate, and talc. It may also contain lubricants such as light anhydrous silicic acid, hydrated silicon dioxide, sucrose fatty acid ester, and hydrogenated oil; surfactants such as glycerin fatty acid ester, sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether, sodium lauryl sulfate, and polyoxyethylene polyoxypropylene glycol; sweeteners such as aspartame, saccharin, sodium saccharin, acesulfame potassium, sucralose, thaumatin, monk fruit extract, sorbitol, sucrose, glucose, and maltitol; flavoring agents such as citric acid, sodium citrate, tartaric acid, DL-malic acid, glycine, and DL-alanine; fragrances such as strawberry, lemon, lemon-lime, orange, l-menthol, and peppermint oil; and colorants such as yellow ferric oxide, ferric oxide, edible tar dyes, and natural pigments.

[0020] In this embodiment, the orally disintegrating tablet containing linagliptin can suppress the bitter taste derived from linagliptin by including carmellose calcium, croscarmellose sodium, carmellose, or sodium starch glycolate as a disintegrant.

[0021] In the present embodiment, the linagliptin-containing orally disintegrating tablet can be produced according to a production method known in the pharmaceutical field. The method for producing the linagliptin-containing orally disintegrating tablet in the present embodiment comprises first homogeneously mixing linagliptin and an additive selected from the above, and tableting the resulting mixture. However, the method is not limited thereto, and a mixture comprising linagliptin and one or more additives selected from the group consisting of carmellose calcium, croscarmellose sodium, carmellose, and sodium starch glycolate may be pre-granulated before use. The granulated product may optionally contain additives such as excipients, binders, disintegrants capable of suppressing the bitterness derived from linagliptin, surfactants, sweeteners, flavoring agents, perfumes, and coloring agents. Alternatively, a granulated product containing no linagliptin may be used. The granulation method may be any method known in the pharmaceutical field, and examples thereof include agitation granulation, fluid bed granulation, tumbling granulation, compression granulation, extrusion granulation, melt granulation, and spray granulation. As the granulation method, the agitation granulation method or the fluid bed granulation method is simple and more preferable.

[0022] In the present embodiment, the linagliptin-containing orally disintegrating tablet can be produced by compression molding with a commonly used tableting machine. For molding, any shape can be adopted, and for example, it can be molded into a tablet shape, an oval shape, a spherical shape, or a rod shape.

[0023] The method for producing the linagliptin-containing orally disintegrating tablet in the present embodiment can suppress the bitterness derived from linagliptin by adding carmellose calcium, croscarmellose sodium, carmellose, or sodium starch glycolate as a disintegrant. [Examples]

[0024] An example of the method for producing the linagliptin-containing orally disintegrating tablet according to the present invention is shown below, but this description is merely an example and is not intended to be limiting thereto.

[0025] (Example 1) For every 5.0 g of linagliptin, 99.1 g of anhydrous calcium hydrogen phosphate (GS: Kyowa Chemical Industry), 84.0 g of crystalline cellulose (Ceolus PH102: Asahi Kasei), 4.5 g of carmellose calcium (ECG505: Nichirin Chemical Industry), 15.0 g of aspartame (Ajinomoto), and 0.9 g of light anhydrous silicic acid (Aerosil 200: Nippon Aerosil) were mixed in a polyethylene bag. The mixture was sieved through a No. 30 sieve, and 1.5 g of magnesium stearate (Taihei Chemical Industry) was added to obtain a powder before tableting. The powder was then compressed into tablets using a rotary tablet press (VELA5: Kikusui Seisakusho) to obtain orally disintegrating tablets containing linagliptin, each containing 210.0 mg and 3.5 mm in thickness.

[0026] (Example 2) An orally disintegrating tablet containing linagliptin, with a thickness of 3.5 mm and containing 210.0 mg per tablet, was obtained using the same method as in Example 1, except that carmellose calcium was replaced with croscarmellose sodium (Kiccolate ND-2HS: Nichirin Chemical Industry).

[0027] (Comparative Example 1) An orally disintegrating tablet containing linagliptin, with a thickness of 3.5 mm and containing 210.0 mg per tablet, was obtained using the same method as in Example 1, except that anhydrous calcium hydrogen phosphate (GS: Kyowa Chemical Industry) was added instead of carmellose calcium (ECG505: Nichirin Chemical Industry).

[0028] (Physical properties of orally disintegrating tablets containing linagliptin) The orally disintegrating tablets containing linagliptin described above were evaluated for their pharmaceutical properties by measuring disintegration time and sensory evaluation. Disintegration time was measured according to the disintegration test method of the 17th edition of the Japanese Pharmacopoeia, and the results of the measurements for 6 tablets were calculated. Oral disintegration time was measured by sensory evaluation, and the results of the measurements for 1 tablet were calculated. For sensory evaluation, bitterness was evaluated on a 4-point scale (+++: very bitter, ++: bitter, +: slightly bitter, ±: hardly bitter), and the results of the measurements for 2 tablets were calculated. Table 1 shows the disintegration time (sec), oral disintegration time (sec), and bitterness (sensory evaluation) for Examples 1 and 2 and Comparative Example 1.

[0029] [Table 1]

[0030] As shown in Table 1, the linagliptin-containing orally disintegrating tablets in Examples 1 and 2, which contained carmellose calcium or croscarmellose sodium as a disintegrant, both showed good disintegration time, in-oral disintegration time, and sensory evaluation. On the other hand, the linagliptin-containing orally disintegrating tablet in Comparative Example 1, which did not contain a disintegrant, showed delayed disintegration time and in-oral disintegration time, and was unable to suppress bitterness.

[0031] (Example 3) For every 5.0 g of linagliptin, 99.1 g of anhydrous calcium hydrogen phosphate (GS: Kyowa Chemical Industry), 84.0 g of crystalline cellulose (Ceolus PH102: Asahi Kasei), 4.5 g of carmellose calcium (ECG505: Nichirin Chemical Industry), 15.0 g of aspartame (Ajinomoto), and 0.9 g of light anhydrous silicic acid (Aerosil 200: Nippon Aerosil) were mixed in a polyethylene bag. The mixture was sieved through a No. 30 sieve, and 1.5 g of magnesium stearate (Taihei Chemical Industry) was added to obtain a powder before tableting. The powder was then compressed into tablets using a rotary tablet press (VELA5: Kikusui Seisakusho) to obtain orally disintegrating tablets containing linagliptin, each containing 210.0 mg and 3.4 mm in thickness.

[0032] (Example 4) An orally disintegrating tablet containing linagliptin, with a thickness of 3.4 mm and containing 210.0 mg per tablet, was obtained using the same method as in Example 3, except that the amount of carmellose calcium was changed to 9 g and the amount of anhydrous calcium hydrogen phosphate was reduced accordingly.

[0033] (Example 5) An orally disintegrating tablet containing linagliptin, with a thickness of 3.4 mm and containing 210.0 mg per tablet, was obtained using the same method as in Example 3, except that the amount of carmellose calcium was changed to 20 g and the amount of anhydrous calcium hydrogen phosphate was reduced accordingly.

[0034] (Example 6) For every 3.0 g of linagliptin, 60.36 g of anhydrous calcium hydrogen phosphate (GS: Kyowa Chemical Industry), 50.4 g of crystalline cellulose (Ceolus PH102: Asahi Kasei), 1.5 g of croscarmellose sodium (Kiccolate ND-2HS: Nichirin Chemical Industry), 9.0 g of aspartame (Ajinomoto), and 0.54 g of light anhydrous silicic acid (Aerosil 200: Nippon Aerosil) were mixed in a polyethylene bag. The mixture was sieved through a No. 30 sieve, and 1.2 g of magnesium stearate (Taihei Chemical Industry) was added to obtain a powder before tableting. Subsequently, the powder before tableting was compressed into tablets using a rotary tablet press (VELA5: Kikusui Seisakusho) to obtain orally disintegrating tablets containing linagliptin, each containing 210.0 mg and with a thickness of 3.4 mm.

[0035] (Example 7) An orally disintegrating tablet containing linagliptin, with a thickness of 3.4 mm and containing 210.0 mg per tablet, was obtained using the same method as in Example 3, except that carmellose calcium was replaced with croscarmellose sodium (Kiccolate ND-2HS: Nichirin Chemical Industry Co., Ltd.), magnesium stearate was changed to 2.0 g, and anhydrous calcium hydrogen phosphate was reduced accordingly.

[0036] (Example 8) An orally disintegrating tablet containing linagliptin, with a thickness of 3.4 mm and containing 210.0 mg per tablet, was obtained using the same method as in Example 7, except that the amount of croscarmellose sodium was changed to 9 g and the amount of anhydrous calcium hydrogen phosphate was reduced accordingly.

[0037] (Example 9) An orally disintegrating tablet containing linagliptin, with a thickness of 3.4 mm and containing 210.0 mg per tablet, was obtained using the same method as in Example 7, except that the amount of croscarmellose sodium was changed to 20 g and the amount of anhydrous calcium hydrogen phosphate was reduced accordingly.

[0038] (Example 10) For every 5.0 g of linagliptin, 84.1 g of anhydrous calcium hydrogen phosphate (GS: Kyowa Chemical Industry), 73.0 g of crystalline cellulose (Ceolus PH102: Asahi Kasei), 30.0 g of croscarmellose sodium (Kiccolate ND-2HS: Nichirin Chemical Industry), 15.0 g of aspartame (Ajinomoto), and 0.9 g of light anhydrous silicic acid (Aerosil 200: Nippon Aerosil) were mixed in a polyethylene bag. The mixture was sieved through a No. 30 sieve, and 2.0 g of magnesium stearate (Taihei Chemical Industry) was added to obtain a powder before tableting. The powder was then compressed into tablets using a rotary tablet press (VELA5: Kikusui Seisakusho) to obtain orally disintegrating tablets containing linagliptin, each containing 210.0 mg and 3.5 mm in thickness.

[0039] (Comparative Example 2) An orally disintegrating tablet containing linagliptin, with a thickness of 3.4 mm and containing 210.0 mg per tablet, was obtained using the same method as in Example 3, except that carmellose calcium was replaced with sodium starch glycolate (Primojel: DFE pharma).

[0040] (Example 11) An orally disintegrating tablet containing linagliptin, with a thickness of 3.4 mm and containing 210.0 mg per tablet, was obtained using the same method as in Comparative Example 2, except that the amount of sodium starch glycolate was changed to 10 g and the amount of anhydrous calcium hydrogen phosphate was reduced accordingly.

[0041] (Example 12) An orally disintegrating tablet containing linagliptin, with a thickness of 3.4 mm and containing 210.0 mg per tablet, was obtained using the same method as in Comparative Example 2, except that the amount of sodium starch glycolate was changed to 20 g and the amount of anhydrous calcium hydrogen phosphate was reduced accordingly.

[0042] (Example 13) An orally disintegrating tablet containing linagliptin, with a thickness of 3.4 mm and containing 210.0 mg per tablet, was obtained using the same method as in Example 3, except that carmellose calcium was replaced with carmellose (NS-300: Nichirin Chemical Industry).

[0043] (Example 14) An orally disintegrating tablet containing linagliptin, with a thickness of 3.4 mm and containing 210.0 mg per tablet, was obtained using the same method as in Example 13, except that the amount of carmellose was changed to 10 g and the amount of anhydrous calcium hydrogen phosphate was reduced accordingly.

[0044] (Example 15) An orally disintegrating tablet containing linagliptin, with a thickness of 3.4 mm and containing 210.0 mg per tablet, was obtained using the same method as in Example 13, except that the amount of carmellose was changed to 20 g and the amount of anhydrous calcium hydrogen phosphate was reduced accordingly.

[0045] (Comparative Example 3) An orally disintegrating tablet containing linagliptin, with a thickness of 3.4 mm and containing 210.0 mg per tablet, was obtained using the same method as in Example 3, except that carmellose calcium was replaced with crospovidone (Kollidon CL-F:BASF).

[0046] (Comparative Example 4) An orally disintegrating tablet containing linagliptin, with a thickness of 3.4 mm and containing 210.0 mg per tablet, was obtained using the same method as in Comparative Example 3, except that the amount of crospovidone was changed to 20 g and the amount of anhydrous calcium hydrogen phosphate was reduced accordingly.

[0047] (Comparative Example 5) Orally disintegrating tablets containing linagliptin, each containing 210.0 mg and 3.4 mm in thickness, were obtained using the same method as in Example 3, except that the amount of anhydrous calcium hydrogen phosphate was increased instead of adding a disintegrant.

[0048] (Physical properties of orally disintegrating tablets containing linagliptin) The orally disintegrating tablets containing linagliptin described above were evaluated for their pharmaceutical properties by measuring disintegration time and sensory evaluation. Disintegration time was measured according to the disintegration test method of the 17th edition of the Japanese Pharmacopoeia, and the results of the measurements for 6 tablets were calculated. For sensory evaluation, bitterness was assessed on a 4-point scale (+++: very bitter, ++: bitter, +: slightly bitter, ±: hardly bitter), and the results of the measurements for 2 tablets were calculated. Table 2 shows the disintegration time (sec) and bitterness (sensory evaluation) for Examples 3-15 and Comparative Examples 2-5.

[0049] [Table 2]

[0050] As shown in Table 2, the linagliptin-containing orally disintegrating tablets in Examples 3 to 15, in which carmellose calcium, croscarmellose sodium, sodium starch glycolate, or carmellose were added as disintegrants, all exhibited good disintegration time and sensory evaluation. Comparing Examples 3 to 5, in which carmellose calcium was added, the amount of carmellose calcium added was preferably 0.9 parts by weight or more, and more preferably 1.8 parts by weight or more, per 1 part by weight of linagliptin. Comparing Examples 6 to 10, in which croscarmellose sodium was added, the amount of croscarmellose sodium added was preferably 0.5 parts by weight or more, more preferably 0.9 parts by weight or more, and more preferably 1.8 parts by weight or more, per 1 part by weight of linagliptin. Comparing Examples 13 to 15, in which carmellose was added, the amount of carmellose added was preferably 0.9 parts by weight or more, and more preferably 2.0 parts by weight or more, per 1 part by weight of linagliptin. Comparing Examples 11, 12, and Comparative Example 2, in which sodium starch glycolate was added, it was found that the amount of sodium starch glycolate added is preferably 2.0 parts by weight or more, and more preferably 4.0 parts by weight or more, per 1 part by weight of linagliptin. On the other hand, the linagliptin-containing orally disintegrating tablets in Comparative Examples 3 and 4, which contained crospovidone as a disintegrant, had a good disintegration time, but could not suppress bitterness. Furthermore, the linagliptin-containing orally disintegrating tablet in Comparative Example 5, which did not contain a disintegrant, had a delayed disintegration time and could not suppress bitterness.

[0051] (Example 16) For every 5.0g of linagliptin, 135.7g of D-mannitol (Mannit P: Mitsubishi Corporation Life Sciences), 17.0g of crystalline cellulose (Ceolus PH101: Asahi Kasei), 8.5g of low-substituted hydroxypropyl cellulose (NBD-022: Shin-Etsu Chemical), 3.4g of crospovidone (CL-F: BASF), 3.4g of crospovidone (CL-M: BASF), 20.0g of croscarmellose sodium (Kiccolate ND-2HS: Nichirin Chemical Industry), and 15.0g of aspartame (Ajinomoto) were mixed in a mortar, then 50g of purified water was added and kneaded. After drying in a shelf-type dryer (MO-921: Toyama Sangyo), the mixture was sieved through a No. 22 sieve, and 2.0g of magnesium stearate (Taihei Chemical Industry) was mixed to obtain a powder before tableting. Subsequently, the powder was compressed into tablets using a rotary tablet press (VELA5: Kikusui Seisakusho) to obtain orally disintegrating tablets containing linagliptin, each containing 210.0 mg and measuring 4.0 mm in thickness.

[0052] (Example 17) An orally disintegrating tablet containing linagliptin, with a thickness of 4.0 mm and containing 210.0 mg per tablet, was obtained using the same method as in Example 16, except that croscarmellose sodium was replaced with carmellose calcium (ECG-505: Nichirin Chemical Industry).

[0053] (Example 18) An orally disintegrating tablet containing linagliptin, with a thickness of 4.0 mm and containing 210.0 mg per tablet, was obtained using the same method as in Example 16, except that croscarmellose sodium was replaced with carmellose (NS-300: Nichirin Chemical Industry).

[0054] (Example 19) An orally disintegrating tablet containing linagliptin, with a thickness of 4.1 mm and containing 210.0 mg per tablet, was obtained using the same method as in Example 16, except that croscarmellose sodium was replaced with sodium starch glycolate (Primogel: DFE Pharma).

[0055] (Comparative Example 6) An orally disintegrating tablet containing linagliptin, with a thickness of 4.1 mm and containing 210.0 mg per tablet, was obtained using the same method as in Example 16, except that croscarmellose sodium was replaced with crospovidone (CL-F:BASF).

[0056] (Comparative Example 7) An orally disintegrating tablet containing linagliptin, with a thickness of 4.0 mm and containing 210.0 mg per tablet, was obtained using the same method as in Example 16, except that D-mannitol was added instead of croscarmellose sodium.

[0057] (Example 20) For every 10.0g of linagliptin, 271.4g of D-mannitol (Mannit P: Mitsubishi Corporation Life Sciences), 34.0g of crystalline cellulose (Ceolus PH101: Asahi Kasei), 17.0g of low-substituted hydroxypropyl cellulose (NBD-022: Shin-Etsu Chemical), 6.8g of crospovidone (CL-F: BASF), 6.8g of crospovidone (CL-M: BASF), 40.0g of croscarmellose sodium (Kiccolate ND-2HS: Nichirin Chemical Industry), and 30.0g of aspartame (Ajinomoto) were mixed in a fluid bed granulator (MP-01: Powrec). After mixing, 300g of purified water was sprayed and the mixture was granulated. After drying, it was sieved through a No. 22 sieve, and 4.0g of magnesium stearate (Taihei Chemical Industry) was mixed to obtain a powder before tableting. Subsequently, the powder was compressed into tablets using a rotary tablet press (VELA5: Kikusui Seisakusho) to obtain orally disintegrating tablets containing linagliptin, each containing 210.0 mg and measuring 4.1 mm in thickness.

[0058] (Physical properties of orally disintegrating tablets containing linagliptin) The orally disintegrating tablets containing linagliptin described above were evaluated for their pharmaceutical properties by measuring disintegration time and sensory evaluation. Disintegration time was measured according to the disintegration test method of the 17th edition of the Japanese Pharmacopoeia, and the results of the measurements for 6 tablets were calculated. For sensory evaluation, bitterness was assessed on a 4-point scale (+++: very bitter, ++: bitter, +: slightly bitter, ±: hardly bitter), and the results of the measurements for 2 tablets were calculated. Table 3 shows the disintegration time (sec) and bitterness (sensory evaluation) for Examples 16-20 and Comparative Examples 6 and 7.

[0059] [Table 3]

[0060] As shown in Table 3, the linagliptin-containing orally disintegrating tablets according to Examples 16-20, in which croscarmellose sodium, carmellose calcium, carmellose, or sodium starch glycolate were added as disintegrants, all received good sensory evaluations, similar to Examples 5, 9, 12, and 15. On the other hand, the linagliptin-containing orally disintegrating tablet according to Comparative Example 6, which contained crospovidone as a disintegrant, failed to suppress bitterness. Similarly, the linagliptin-containing orally disintegrating tablet according to Comparative Example 7, which did not contain a disintegrant, also failed to suppress bitterness. It was found that the manufacturing method of the linagliptin-containing orally disintegrating tablets in this embodiment yielded similar results to the direct compression method whether using the kneading method or the fluid bed granulation method. There was variability in the disintegration time, which is thought to be due to the amount of disintegrant being greater than that normally used in granulation, resulting in stronger moldability than disintegration properties of the disintegrant.

Claims

1. Linagliptin and, An additive comprising one or more selected from the group consisting of carmellose calcium and carmellose, Orally disintegrating tablets containing linagliptin.

2. The linagliptin-containing orally disintegrating tablet according to claim 1, wherein the additive comprises 0.9 parts by weight or more per 1 part by weight of linagliptin.

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